Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects
The G-protein-coupled receptor kinase 2 (GRK2) is an important regulator of inflammation and pathological macrophage phenotype in a variety of diseases. We hypothesize that Gβγ-GRK2 signaling promotes the early inflammatory response and chondrocyte loss in osteoarthritis (OA). Using the destabilizat...
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| Format: | Article |
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MDPI AG
2022-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/14/7933 |
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| author | Vengadeshprabhu Karuppagounder William Pinamont Natalie Yoshioka Reyad Elbarbary Fadia Kamal |
| author_facet | Vengadeshprabhu Karuppagounder William Pinamont Natalie Yoshioka Reyad Elbarbary Fadia Kamal |
| author_sort | Vengadeshprabhu Karuppagounder |
| collection | DOAJ |
| description | The G-protein-coupled receptor kinase 2 (GRK2) is an important regulator of inflammation and pathological macrophage phenotype in a variety of diseases. We hypothesize that Gβγ-GRK2 signaling promotes the early inflammatory response and chondrocyte loss in osteoarthritis (OA). Using the destabilization of the medial meniscus (DMM) model in 12-week-old male C57BL/6 mice, we determined the role of Gβγ-GRK2 signaling in synovitis, macrophage activation, and OA development. We achieved Gβγ-GRK2 inhibition at the time of DMM by administering the Gβγ inhibitor “gallein” and the GRK2 inhibitor “paroxetine” daily, starting from 2 days before DMM surgery, for a duration of 1 or 12 weeks. Synovial and cartilage structural changes were evaluated by histomorphometry, and molecular events and macrophage activation were examined. We studied the direct role of Gβγ-GRK2 in synovitis and macrophage activation in vitro using SW982 and THP1 cells. Continuous Gβγ-GRK2 inhibition initiated at the time of DMM attenuated OA development and decreased chondrocyte loss more effectively than delayed treatment. GRK2 expression and the M1 macrophage phenotype were elevated in the inflamed synovium, while early gallein and paroxetine treatment for 1 and 12 weeks following DMM resulted in their reduction and an upregulated M2 macrophage phenotype. In vitro experiments showed that Gβγ-GRK2 inhibition attenuated synoviocyte inflammation and the M1 phenotype. We show that early Gβγ-GRK2 inhibition is of higher therapeutic efficacy in OA than delayed inhibition, as it prevents OA development by inhibiting the early inflammatory response. |
| first_indexed | 2024-03-09T10:17:15Z |
| format | Article |
| id | doaj.art-57e2e717a6fd4f81a56e77fad26194c2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T10:17:15Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-57e2e717a6fd4f81a56e77fad26194c22023-12-01T22:16:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012314793310.3390/ijms23147933Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective EffectsVengadeshprabhu Karuppagounder0William Pinamont1Natalie Yoshioka2Reyad Elbarbary3Fadia Kamal4Center for Orthopaedic Research and Translational Science (CORTS), Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USACenter for Orthopaedic Research and Translational Science (CORTS), Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USACenter for Orthopaedic Research and Translational Science (CORTS), Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USACenter for Orthopaedic Research and Translational Science (CORTS), Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USACenter for Orthopaedic Research and Translational Science (CORTS), Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USAThe G-protein-coupled receptor kinase 2 (GRK2) is an important regulator of inflammation and pathological macrophage phenotype in a variety of diseases. We hypothesize that Gβγ-GRK2 signaling promotes the early inflammatory response and chondrocyte loss in osteoarthritis (OA). Using the destabilization of the medial meniscus (DMM) model in 12-week-old male C57BL/6 mice, we determined the role of Gβγ-GRK2 signaling in synovitis, macrophage activation, and OA development. We achieved Gβγ-GRK2 inhibition at the time of DMM by administering the Gβγ inhibitor “gallein” and the GRK2 inhibitor “paroxetine” daily, starting from 2 days before DMM surgery, for a duration of 1 or 12 weeks. Synovial and cartilage structural changes were evaluated by histomorphometry, and molecular events and macrophage activation were examined. We studied the direct role of Gβγ-GRK2 in synovitis and macrophage activation in vitro using SW982 and THP1 cells. Continuous Gβγ-GRK2 inhibition initiated at the time of DMM attenuated OA development and decreased chondrocyte loss more effectively than delayed treatment. GRK2 expression and the M1 macrophage phenotype were elevated in the inflamed synovium, while early gallein and paroxetine treatment for 1 and 12 weeks following DMM resulted in their reduction and an upregulated M2 macrophage phenotype. In vitro experiments showed that Gβγ-GRK2 inhibition attenuated synoviocyte inflammation and the M1 phenotype. We show that early Gβγ-GRK2 inhibition is of higher therapeutic efficacy in OA than delayed inhibition, as it prevents OA development by inhibiting the early inflammatory response.https://www.mdpi.com/1422-0067/23/14/7933osteoarthritissynovitisG-protein-coupled receptor kinase 2therapeutics |
| spellingShingle | Vengadeshprabhu Karuppagounder William Pinamont Natalie Yoshioka Reyad Elbarbary Fadia Kamal Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects International Journal of Molecular Sciences osteoarthritis synovitis G-protein-coupled receptor kinase 2 therapeutics |
| title | Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects |
| title_full | Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects |
| title_fullStr | Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects |
| title_full_unstemmed | Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects |
| title_short | Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects |
| title_sort | early gβγ grk2 inhibition ameliorates osteoarthritis development by simultaneous anti inflammatory and chondroprotective effects |
| topic | osteoarthritis synovitis G-protein-coupled receptor kinase 2 therapeutics |
| url | https://www.mdpi.com/1422-0067/23/14/7933 |
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